The human lung has about 300 million alveoli that facilitate gas exchange between inhaled air and blood to maintain respiration. Because of the critical functions the alveoli perform, it is essential to maintain the integrity of the alveoli. Perturbations that injure and weaken alveoli can lead to lung collapse resulting in respiratory distress and possible death. The stability of the alveoli is maintained by surfactant, a lipid-protein complex produced and secreted by the alveolar type II and Clara (bronchiolar) epithelial cells. Surfactant stabilizes alveoli by reducing surface tension in the lung. Additionally surfactant plays important roles in the control of host defense and inflammation to protect lung from damage. Reduced levels and activity of surfactant contribute to the development of lung injury in newborn and acute respiratory distress syndromes (RDS), bacterial and viral lung infections, and occupational lung diseases. Thyroid transcription factor-1 (TTF-1), a transcription factor essential for lung development, controls surfactant protein expression. Because of the important roles that TTF-1 plays in the lung, abnormal levels of TTF-1 probably contribute to the development of lung diseases. Interleukin-8 (IL-8) is a chemokine that is a potent chemoattractant for neutrophils, T cells and other immune cells. IL-8 levels are directly correlated with neutrophil content and severity of lung injury in inflammatory lung diseases. A number of agents such as tumor necrosis factor-alpha (TNF-alpha), bioactive lipids, and reactive nitric and oxygen species serve as causative agents for altered production of surfactant protein, TTF-1 and IL-8 in lung diseases. A better understanding of cellular pathways and mechanisms mediating aberrant production of surfactant protein, TTF-1 and IL-8 is important for the development of novel drugs and treatments for lung diseases.

Research Overview:

Transcriptional and posttranscriptional (mRNA stability) mechanisms serve as key regulatory steps in the control of gene expression. Cell signaling pathways control gene expression to maintain tissue homeostasis. Our research is aimed at understanding cellular pathways and gene regulatory mechanisms controlling surfactant protein, TTF-1 and IL-8 levels in normal and injured lung. We use primary lung cells, lung cell lines and animal models of lung injury to understand mechanisms mediating altered productions of surfactant protein, TTF-1 and IL-8 and development of lung disease.

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